CN1235825A

CN1235825A - Sustained release capsule and formulations

Info

Publication number: CN1235825A
Application number: CN99106439A
Authority: CN
Inventors: L·B·洛; C·J·麦克阿瑟
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1991-04-05
Filing date: 1999-04-24
Publication date: 1999-11-24
Also published as: NZ242225A; PT102360A; RU2114577C1; EP0715847A3; EP0715847A2; IL118195A0; US5277912A; FI111602B; NO921304L; PT102360B; US5562915A; EP0507629B1; DK0507629T3; IL118192A; KR100205666B1; DE69216891T2; FI921493A0; CA2065084A1; ES2096717T3; MY112079A

Abstract

A sustained release capsule adapted to be inserted into the rumen of a ruminant animal and means for retention of the capsule in the rumen.

Description

Slow releasing capsule and preparation

The invention relates to a kind of slow releasing capsule, this capsule can insert its cud from the esophagus of ruminant, and remains in bioactivator or the compositions that constantly discharges in the cud in incapsulating for a long time.

General a kind of device is characterized in that following capsule at present, this capsule comprises a hollow body of an end perforate, one by spring driving treatment plunger with solid composite of adorning in perforate passing pipe, around opening has an annular flange, can prevent that driving device from releasing body to solid composite, the other end of battalion's body has a sealing cap, is connected with two elastic arms on this medicated cap.

A problem of existing apparatus is that described medicated cap is to be welded on the hollow body, and welding often is invalid, can make water and gastric juice enter capsule.The treatment component is again a kind of moisture absorption component usually, and swollen when water exists finally makes capsules break.Welding badly also can cause capsules break, this is undesirable, because therapeutic combination that should slow release all discharges suddenly, may cause animal dead.

Another problem goes out the pore on medicated cap.Pore needs, and like this, can not form vacuum when the capsule administration.But before the capsule administration and during the administration, lubricating oil might pass through the pore seepage, is unfavorable by pore loss lubricating oil.Lubricating oil seals, and one deck Obstruct membrane is provided.Any loss of lubricating oil all can cause therapeutic combination not according to quantitative release.

Another problem of existing apparatus is that the crimping on the plunger makes poor sealing.It is poor to seal, and along with plunger moves along body, water enters capsule, produces friction thus, and this friction causes therapeutic combination not according to quantitative release.In addition, the malfunctioning meeting of plunger causes water to enter capsule, thereby causes the therapeutic combination swollen, increases friction.

Therefore, need a kind of slow releasing capsule that can in cud, be in effective sealing state between demurrage all the time.The ruminant that also needs slow releasing capsule continuously to put in a suitable place to breed to the grassland discharges treatment or growth promoting composition as cattle or sheep.

The purpose of this invention is to provide a kind of sealing property of having improved, have the plunger that is easy to move, can discharge the slow releasing capsule of therapeutic combination continuously by capsule.

According to first kind of embodiment of the present invention, a kind of capsule of using a compositions to ruminant is provided, this capsule comprises: the tubular bodies and a medicated cap of a band staving, described medicated cap and staving have cylindrical portions may respectively, one is enclosed within formation tight seal in another, one of them barrel sets up spaced all grooves separately, has corresponding intervals circumference ripple and described groove to agree with on another stack shell, and a stack shell partly also has a circle sealing ring.

According to second kind of embodiment of the present invention, a kind of device of using a compositions to ruminant is provided, this device comprises a seal capsule, have at least an elasticity to be detained arm on the described capsular outer surface, it has a projection this delay arm on capsular arm surface, arm is flexible that this projection is contacted with a capsular part, said this part can be penetrated the formation pore by projection.

According to the third embodiment of the present invention, a kind of capsule of using a compositions to ruminant is provided, this capsule comprises that an end is provided with a round barrel shape body of release aperture, described compositions is between plunger and perforate, press to the plunger of perforate by a spring, around its outer surface one circle or multi-turn groove arranged on the plunger.

According to the 4th kind of embodiment of the present invention, provide a kind of and used the device of a compositions to ruminant, this device comprises a tubular capsule, this capsular end has release aperture, and the other end normally seals, a plunger is arranged in the cylindrical shell, this plunger is pushed release aperture to by a turn.The tight contact plunger of one end of spring, the other end is fixed on the edge of a thimble.Said thimble has a core, and an end is that awl is circular, and the other end forms flange, and the blunt end of thimble is inserted spring, and flange is between spring and the capsule blind end.

According to the 5th kind of embodiment of the present invention, a kind of method of combination of two-body capsule is provided, said capsule is used for using compositions to ruminant, this method may further comprise the steps: first utricule that compositions is incapsulated, one plunger is inserted this main capsule body, one thimble is injected to a helical spring outer end, said thimble comprises a cylindrical shell, one end is the round end shape, at the other end one flange is arranged, blunt end and cylindrical shell are in the turn, flange is fixed on the spring outer end, the inner of spring is inserted above-mentioned first utricule and is inserted into the plunger place, make second portion capsule and first's engages and seals, make spring compress to such an extent that make wherein a part of spring holder on described cylindrical shell thus.

According to the 6th kind of embodiment of the present invention, a kind of slow releasing capsule is provided, this capsule can insert its cud from the esophagus of ruminant, and long-term existence is in cud, constantly discharges the bioactive composition that is contained in the capsule, and this capsule comprises:

One slender tube body and that comprises a pipe can guarantee that body one end seals the end cap of bioactive composition basically, the capsular other end is to discharge end, body has a perforate to discharge said composition to cud at the release end, described capsule also comprise several link to each other with described medicated cap or with medicated cap be holistic delay arm, these arms can outwards be stretched by medicated cap and make capsule be stranded in cud, these arms still are resilient, can bend towards body by extended position, thereby be positioned at the body side, capsule can be inserted by the animal esophagus.Elastic arm is stretched out by body, becomes 75 ° of-90 ° of angles with the body axis usually, for each elastic arm, described medicated cap has a positive camber that designs with respect to described arm, like this, and when the crook of the arm during to body, arm contacts with curved surface, and the bending of curved surface control arm makes its unlikely rapid bending.When capsule arrived cud, described arm can return to extended position, was characterised in that described medicated cap is fixed on the said end by at least two circle ripples, has at least one sealing ring between the ripple.

Can be equipped with one in the capsule body scribbles the labyrinth type plunger of lubricating oil and when the capsule administration, pushes the device that plunger makes active compound move towards release aperture to discharging end.

Preferred plunger can slide at the body internal sealed, except release aperture, can stop gastric juice to enter the active compound donor.

At least one weakened region is generally arranged on the described medicated cap, said arm has at least one projection on the face adjacent with medicated cap, therefore, when the crook of the arm during to the body side, projection (or several) engage with the medicated cap wall, cause at least one this regional breakdown on the said wall, produce at least one pore thus, make plunger move the middle any vacuum that forms and released.

The slow releasing capsule that has the positiver sealing device problem that how to provide is provided.The present invention does like this, promptly provides a kind of gastric juice that prevents to come in contact with the compositions bolt except other zone release aperture.Because compositions discharges, remaining compositions bolt is pushed to release aperture, and the space of suppository back may charge into gastric juice in the capsule, makes suppository swollen or corrosion in the capsule thus.

Preferred implementation of the present invention has solved this problem, and controls release administration for a long time and very equably thus better.More particularly, in preferred implementations more of the present invention, the intravital dosing holes of capsule tube shape is enclosed by the annular continuous surface of a truncated cone, and the compositions bolt in the capsule forms sealing near this surface.

In a better embodiment of the present invention, the labyrinth type plunger advances the compositions bolt to perforate, and takes action to become sealed with inboard wall of tube body.Lubricating oil is filled in the groove of plunger, plunger is moved to perforate and does not produce friction.There is not friction to prevent that promptly therapeutic combination is not according to the phenomenon that quantitatively discharges.

By another better embodiment, the projection that is provided with on the capsule arm can make the tenuity on the medicated cap wall break and form pore.In this preferred capsular administration process, projection is lived port sealing, thereby has prevented the seepage of lubricating oil.When capsule was positioned at cud, said arm trailed, thereby made projection break away from pore, prevented the formation of vacuum therefrom.

In another preferred embodiment, propulsion plant is a helical spring, and this spring can prevent distortion by a thimble is put into it.

The operable active ingredient of capsule of the present invention comprises any active ingredient that is suitable for the ruminant administration.Preferably those can directly enter the component of cud administration on request.

The active ingredient that is suitable for comprises polyether antibiotic or ionophore, glycopeptide antibiotic anthelmintic and end epizoa insecticide.

Polyether antibiotic or ionophore can be used as growth promoter, medical preparation for making breast plump, and can be used as the therapeutic agent of bloat.Operable polyether antibiotic comprises those antibiotic that produced by the microorganism streptomyces.These antibiotic being characterised in that have diversified cyclic ethers in its structure.Its kind can be referring to Kirk-Othmer:Encyclopedia of chemical Teehnology, the 3rd volume, the 3rd edition (John Wiley﹠amp; Sons, 1978), the 47th page reaches hereinafter; Annual Reportsin Medical Chemistry Volume10 (academic press, N.Y, 1878), the 246th page reaches hereinafter; J.Chrom.Lib., (Elsevier ScientificPublishing CO., N.Y.1978) the 488th page reaches hereinafter 15 volumes.

The typical example that can be used for the polyether antibiotic of the present composition comprises ruminates the propionic ester improving agent such as monensin (comprises A, the various factors of B and C, alkali metal salt is as can not shoestring sodium, and various esters), ionomycin, laidlomycin, nigericin, grisorixin, dianemycin, chemical compound 51,532, lenoremycin, Salinomycin, narasin, Emericid, antibiotic X206, alborixin, septamycin, antibiotic A204, chemical compound 47,224, etheromycin, the Rasa Ria mushroom) (factors A, B, C, D and E), the mould rope of wonderful too sieve, K41, different lasalocid A, lysocellin, tetronasin and antibiotic X-14766A, A23187 and A32887.

Preferred polyether antibiotic comprises monensin, narasin, lasalocid, Salinomycin, A-204, Emericid, X-206, nigericin and dianemycin.Preferred especially monensin, narasin, lasalocid and Salinomycin.

The polyethers that especially preferably uses according to the present invention is a monensin, and it is to improve widely used chemical compound (seeing US3,839,557) aspect the ruminant feed utilization rate.This paper said " monensin " comprises various active factorses, salt such as rumensin and monensin ester such as carbamate or the like.

Glycopeptide antibiotic also can be used as growth promoter, medical preparation for making breast plump and as the therapeutic agent of bloat.They can use separately or be used in combination with polyether antibiotic, and as AU556,299 is described.

Typical this class glycopeptide efficiency of feed utilization improving agent is actaplanin, avoparcin, A35512, A477, RCT, vancomycin, and relevant glycopeptide.

The preferred glycopeptide that can use in the present composition comprises actaplanin, avoparcin, RCT and vancomycin.

Anthelmintic can be used for treating the blood trematodiasis, survives in the trematodiasis in lung, liver and the intestinal, and can treat ascarid in cestode, intestinal ascarid and blood and the tissue or treat several in them simultaneously.Preferred anthelmintic comprises antimony potassium tartrate, bephenium hydroxynaphthoate, bithionol, chloroquine, dichlorophen, diethylcarbamazine citrate, hexyl resorcin, hycanthone mesylate, lucanthone hydrochloride, mebendazole, niclosamide, nitrothiamidazol, piperazine citrate, Pyrantel Pamoate, povan, quinacrine hydrochloride, sodium stibocaptate, antimony ripple labor, tetrachloroethylene, thiabendazole, phenothiazine, hexachlorethane, Carbon bisulfide or benzimidazole.Particularly preferred anthelmintic is a benzimidazole.The benzimidazole example that is suitable for has thiabendazole, albendazole, bonlam, fenbendazole, mebendazole, oxfendazole and oxfendazole.

Preferred end epizoa insecticide is organic phosphate and carbamate, avermectins, Levamisole, thiacetarsamide sodium.

In preparation, add the activity that one or more non-ionic surface active agents can strengthen the active constituent that comprises polyether antibiotic and/or glycopeptide antibiotic.Preferred surfactants is an alcohol ethoxylate.Ethoxylate commonly used be octyl group-, nonyl-and dodecylphenol ethoxylate, the ethoxylate of natural and synthol, saturated and unsaturated fatty acid and block and random copolymer.Alcohol ethoxylate such as Teric ^Series or Pluronic ^PE series or their mixture are preferred.Particularly preferred non-ionic surface active agent is Teric ^12A23, it is the condensation substance of lauryl alcohol (dodecanol) and 23 moles of ethylene oxide.

The siloxanes antifoaming agent also can be added in the preparation to strengthen its performance.Siloxanes can be aqueous for anti-roll dose, also can be anhydrous, and with anhydrous for well.Said antifoaming agent can be the mixture of dimethyl siloxane.As Gensil ^The mixture of series or Rhodorsil series.Particularly preferred siloxanes antifoaming agent is Gensil ^800 or Silbione ^70451.

Can also include emulsifying agent or stabilizing agent in the preparation.Preferred solvent or stabilizing agent comprise glyceride, glyceryl monostearate, distearyl acid six glyceride, mono stearic acid triacyl glycerol, two Palmic acids, ten glyceride, sorbitol ester such as monostearate sorbitol ester, three stearic acid Pyrusussuriensis alcohol esters, or ethoxylation ester such as glyceryl monolaurate, or their mixture.

One typical formulation contains:

Surfactant 50%

Monensin 40%

Glyceride 10%

If typical formulation contains antifoaming agent, it is:

Antifoaming agent 10%

Monensin 40%

Glyceride 50%

Now describe optimal way of the present invention in detail by embodiment and accompanying drawing, wherein:

Fig. 1 is the sectional side elevation of the capsular basic actual ratio of the present invention, is provided with the arm that is detained the wing and represents their normal extension position, the stacked administration position of arm when representing that with dotted line capsule inserts by esophagus with solid line.

Fig. 2 is the sectional view along Fig. 1 2-2 line.

Fig. 3 is the front view of the capsular arm wing and front end.

Fig. 4,5 and 6 is the sectional views along Fig. 3 4-4,5-5,6-6 line.

Fig. 7 is the sectional side elevation that is similar to Fig. 1, but ratio amplified, and the mid portion of staving is omitted, and shown in the capsular fore-end is the part decomposing state.

Fig. 8 illustrates a kind of sketch of giving means that capsule is inserted esophagus by the cattle mouth.

Fig. 9 is the side view of the capsule arm wing and front end.

Figure 10 is the side view of medicated cap.

Figure 11 is the side view of plunger.

Figure 12 is a kind of side view that can be used for preventing the thimble of spring distortion.

Figure 13 is the sectional view of staving along centrage, shows bell.

Slow releasing capsule 8 shown in Fig. 1-7 comprises that one can seal the body 10 of bioactive composition solid core or bolt 32 up for safekeeping.Body 10 has a drum promptly to manage 16 end walls that discharge end with smooth curve and capsule promptly to hold 18 to link to each other usually.Garden bucket or Guan Youyi cylindrical shape part.Not allow gastric juice enter compositions in the capsule in order controlling, promptly 18 to be provided with a narrow circular release aperture 20 at end wall.In order to advance core to release aperture 20 is compositions 32, and therefrom one very long-term between in keep by release aperture and supply with compositions, be provided with a plunger 36 in capsule, the pushing core is a compositions 32, and pushes perforate 20 to by a pressue device such as light-duty helical spring 38.

For holding core is a compositions 32 and end wall is promptly held 18 be sealed and matched, control does not allow gastric juice enter compositions therefrom, and end wall is provided with a release aperture.Inner face 17 engages with smooth bent interface 19 at its circular arc place.Bioactive composition 32 loaded articles are that core is exposed to gastric juice by release aperture 20, therefrom in its contiguous volume-diminished that contacts end face 34 places.Interface 19 is that primary seal contacts with the ora terminalis of the pre-coremaking of compositions, during administration, can keep cambered surface sealing and with the ora terminalis guiding release aperture of loaded article.Dwindle the dissolubility or mobile can the change of the width and the loaded article of the face 17 that engages of end with loaded article, so that the speed that the control load thing feeds to release aperture 20, control the speed of capsule release composition therefrom.The inner of loaded article can be protected and be not exposed in the gastric juice, and as with capsular that end sealing relative with discharging nose end or utilize a sealing-plug, this will be for a more detailed description hereinafter.

For capsule is trapped in the animal cud of institute's administration, on capsule, is provided with several and is detained arm 44.On explanation and preferred as an example, arm 44 are connected body and discharge the relative end of end, also be called front end in the text sometimes.In scheme shown in the drawings, two arms are arranged, and be successive substantially, form a so-called wing 14.

In order to control the degree of crook of the delay arm that is connected on the body, reduce arm thus the pressure that is born, with good grounds arm on the body and the salt face 26 (Fig. 9) that designs, therefore, when the crook of the arm during, contact with curved surface 26 to body, thereby, rather than bend suddenly at junction point with the bending of long arc form.In an illustrational embodiment, that end relative with discharging end is with a hemispherical end medicated cap 12 cappings on the capsule, and the said wing is connected as a single entity with it.The exterior semi-spherical surface of medicated cap is designed to desired curved surface.

Referring to Fig. 7, bucket is promptly managed 16 front end has a circle taper to lead mouthful 22 guide groove 24, and groove can be accepted and be that screw thread is sealed with corresponding ripple on the block 12.Said medicated cap has the hemispherical end wall of linking cylindrical shell 28 usually, and said cylindrical shell 28 preferably has the outer ripple 30 of two circles, leads mouth 22 and groove 24 engagements so that enter the taper of described bucket, guarantees that medicated cap 12 mechanically is connected on the body.General dual damascene can guarantee the sealing of medicated cap 12 and body, thereby prevents that liquid from infiltrating capsule.Good sealing can prevent packing, storage or between the delivery period silicon grease leak from described device.It is complete screw thread 31 that medicated cap 12 also has a sealing ring, and preferably between two ripples (not shown among Fig. 7, as to see Fig. 9 and 10).In one embodiment, the cross section of sealing ring is leg-of-mutton, and its higher primary school is in circumference ripple 30.Bucket is promptly managed prefabricated barrel core 32 administration loaded articles is housed in 16, shape as shown in Figure 1, and this barrel core has nose circle face 34, can form primary seal with the inner face 19 of bucket and cooperate.In Fig. 7, the rear end of shown core 32 promptly discharges end and is in user mode, and wherein, the core end is owing to press to release aperture 20 and prop up end wall and promptly hold 18, absorbs gastric juice and dwindles.On request, the hemispherical ends pars intramuralis of medicated cap 12 has a pair of cross rib 40, for the anti-end of spring 38 provides a flat bearing.

Be detained the wing 14 connector 42 horizontal by one and that be close on the capsule central core region and be connected as one the axial line adjacency of the capsule body of the outermost end core of the described wing 14 and hemisphere body wall 26 with medicated cap 12.The wing 14 is tangential to the central axis of hemispherical medicated cap 12 basically, and has arm 44, and said arm 44 is by oppositely outwards Shen exhibition of junction point, as shown in figs. 1 and 3.Like this, in the embodiment that exemplifies, arm and body axis are at an angle of 90.In order to reduce the stress of arm, each arm all should be in the scope that becomes 75 ° of-90 ° of angles with body.Said arm can the downward elastic bending of curved surface outside the hemispherical of medicated cap 12, and can put down basically that to lean against bucket be on the tube wall, like this, when capsule inserts the animal cud by esophagus, the effective diameter of its cross section can be not bigger than the diameter of section of bucket itself must be too much.When capsule entered cud by esophagus, the arm 44 outer bullets on the wing 14 hindered by forming in the backward channel of esophagus at capsule thus, thereby have been detained capsule to their maximum extension position, have stoped and have ruminated the backward channel that has promptly stoped by cud.

Can think, the position at the outstanding basic right angle of wing arm 44 prevent capsular ruminate and reduce arm in cud degree of crook and stress two aspect superiority is arranged.Except right angle T-shape, as adopt other configuration, unlikely occur between the said arm crooked relatively or to the situation of staving bending.More specifically, this class contraction and user mode are unlikely extremely can make capsular front end enter the position of esophagus two brachiocylloosis.

It is desirable to, the wing 14 is reinforced and made make that its arm 44 is easier to bend towards and be against the capsule sidewall, and be difficult for promptly leaving capsular direction bending in the opposite direction, the situation that may occur when making capsular tail end promptly discharge the end back at needs by esophagus.In some cases, the wing can be molded as little arc, makes its arm 44 towards the bending of capsule afterbody camber, thus, and with it compare to the relevant position by rightabout is curved, only needs a less flexibility can make the crook of the arm be against the capsule sidewall.

The core of the said wing is reinforced, and it is desirable to make asymmetric cross section, to strengthen the forwards crooked resistance to the wing of its arm.As shown in the figure, at the outer surface of the wing vertical rib is set and obtains asymmetric configuration.Therefore, shown in Fig. 3-6, the basic cross section of the wing is the cross section of a bandwidth rectangular sheet spring as shown in Figure 4.Inside by Fig. 4, as shown in Figure 5, two side ribs of erectting along its edge 46 are arranged on the wing, its length extends to most of length place that the capsule bucket is a body 16.Inside again, a center rib 48 that weak point is a little is arranged on the wing, it passes the company connection zone 42 of the wing and medicated cap wall 26.The ideal length of center rib 48 is, when the crook of the arm during on position, its length extends the base portion of hemispherical wall 26 substantially, as shown in Figure 8.Said

rib

46 and 48 can be strengthened the opposing wing 14 towards front curve, makes the wing require the recurvate resistance on the crooked backward sidewall that is placed in capsule staving 16 of arm big towards the resistance ratios of front curve.

In a specific embodiment, its staving of capsule that is used for the cattle administration is about 145.2mm, external diameter 33.35mm, the wide 12.9mm of the wing, long 162.5mm, two side ribs 46 extend 90% of topped chord, center rib 48 is half of side rib length, and the border circular areas diameter that the wing is connected with medicated cap is about 11.2mm.

This configuration of the said wing and structure and and can not only be convenient to capsule by the mutual relation between the hemispherical wall 26 formed capsule curved end and insert and be trapped in cud by esophagus, and can strengthen capsule and tolerate it and be trapped in the various conditions that met with in the cud for a long time.In cud, the capsule and the said wing not only will run into the biochemical condition that it must bear, and to be subjected to from the cud not digest food and normally take food, ruminate with digestion process in cud motion and produce continuously, intensive mechanical pressure.

In a preferred embodiment, projection 50 is arranged on the close medicated cap side of each arm of the wing 14.A pair of protruding 50 are opposite on the arm mutually, and like this, curved during on position when the wing 14, as shown in Figure 8, projection 50 contacts with the curvature portion of hemispherical wall 26.In our embodiment, the inwall 27 of medicated cap 12 is provided with two grooves 52 (Fig. 7), and these two grooves 52 make this two area thickness attenuate of inwall 27, and transparent fenestra 51 is provided.When the curved surface of projection 50 and wall 26 came in contact, fenestra 51 was just adjacent with projection 50, and this projection penetrates fenestra and makes the formation pore.

Shown capsule can be combined easily, promptly, with ready-formed barrel core is that the bucket that compositions 32 is inserted bodys 10 is promptly managed in 16, inject plunger 36 and spring 38 then at the capsule rear portion, the compression spring, medicated cap 12 is pressed into the opening of staving 16, makes the circumference ripple 30 on the medicated cap sealed, form two-way cooperation with the mode and the groove on the staving 24 of interlock.

Before assembling, require lubricating oil such as light siloxane lubricant oil be coated in and barrel promptly manage on 16 the inner surface, or be coated on the outer surface of core 32.This lubricating oil forms primary seal, makes pre-coremaking have certain waterproof action, and forms an Obstruct membrane, prevents that core is adhered on the staving.It also will help to guarantee core 32 in the intravital slip of bucket, and guarantee core 32 at the beginning under light spring 38 pressure effects, and with end wall that is hold 18 to form and be sealed and matched, and compositions remains this cooperation by release aperture between 20 long-term slow-release periods in capsule.

Capsular body 10 and medicated cap 12 all can make things convenient for and use plastic material molded at an easy rate.Certainly, the cud that this class material must be an animal is acceptable, and must have the ability of chemistry, biology and physical condition in the opposing cud.Polyethylene and polyacrylic polymer, or polyacrylic polymer preferably are the materials that is suitable for.

Capsule can be molded as two parts in the usual way, and a part comprises staving and release aperture, requires to reach the inner surface that cross section is a uniformity, makes capsule have predetermined bright clean degree, and makes plunger slidably.Another part is made up of medicated cap, promptly is used for the sealing of front end, and its wing centre section is that part is molded as a whole.

In some instances, need capsule to be trapped in longer a period of time in the cud,, during this section, can regularly give capsule because in some place in the world, cattle is stayed the pasture and tides over this period.Can be more than 200Kg to capsular cattle body weight, the cud of this animal can have the capacity more than 100 liters, therefore, can hold the capsule of the designed size of several the present invention, and long-term the delay.

The available means of giving shown in Figure 8 inserts capsule the cud of cattle easily.This instrument comprises a pipe bucket 60, and its worn-out mouthful of end can be accepted capsule 8, and the wing arm 44 of capsule 8 is on the sidewall that is stacked in its staving 16.In this position, projection 50 engagement fenestras 51 seal, with entering of waterproof or gastric juice.Pipe bucket 60 is positioned on the pipe 62 of band one handle 64, and by handle 62, but the control lead bucket is put into esophagus to an end of capsule 8 by the mouth of animal.Pipe 64 comprises that a thrust rod is a plug 66, and this plug 66 has a plunger 68 at its front end, and a thrust handle 70 is arranged in its outer end, by thrust handle 70, leans on chock plug 68 and can send into esophagus to capsule 10 by bucket 60 releases.When the capsule with stacked arm 44 entered in the esophagus way, capsule can move into cud by esophagus, but esophagus clamping limb 44 is in stowed position, arrives cud up to capsule.Then, described arm to they normally put towards the exhibition position, shown in Fig. 1 solid line, makes capsule be trapped in the cud and worn-out open pore on outside bullet thus.

When the arm 44 of the wing 14 curved during to stowed position, shown in Fig. 1 dotted line, these arms with the camber line form of major radius glossily along the positive camber bending of capsule hemispherical wall 26, thereby not can certain a bit press distortion.When arm was loosened by stowed position in cud, their very fast returning to again on the position capsule axis, that radially outwards stretch separately preferably were with arc, as shown in Figure 1 slightly.In this extended position, the wing is a straight outer surface substantially, prevents that thus capsular front end from entering esophagus, ruminated out by cud.If the capsular other end enters cud, the high-drag of the arm wing of Shen Zhaning and anti-phase bending thereof all will hinder capsule by esophagus so, and hinder therefrom from this position and ruminate out.In addition, wing arm 44 its arms that stretch reach each other and capsule between occupy so wide space angledly, cause the motion of cud unlikely to make the said crook of the arm, and be acute angle, so be not easy to be pressed to capsule owing to said arm reaches each other with staving to capsule.

When beginning pre-coremaking is compositions 32 when injecting bucket and promptly managing 16, and spring 38 is pressed in its ora terminalis, makes it promptly to hold 18 to be and to be sealed and matched with the end wall of bucket, so that the contacting of the end face 34 of restriction gastric juice and core.In normal processes, gastric juice flows to an end of core 32, makes it to soften and dwindle, and core is pushed to the perforate 20 of capsule end wall by spring 38 then.Therefore, capsular end wall 18 is in sealing state in a wide region, and as shown in Figure 7, and gastric juice enters the size that the region area of capsule 32 ends is subject to perforate 20.In contact area, compositions 32 is as entering gastric juice by flushing, erosion and dissolving in the capsule.Simultaneously, because gastric juice or its component flow into the balance that the softening thing of core end will further be kept in the end of core, and pass through spring 38 with continuous holding core moving to release aperture.Like this, one very over a long time in, the contained medicine of in-core can constantly discharge to cud.This injection speed depends in part on compositions core 32, also can be by the configuration control of capsule end wall 18, and this point is very important, and is as shown here and described, particularly by its tapering part that outwards shrinks 17 controls.The width of the size of perforate 20 and the conical surface 17 and the degree of depth can change according to the variation of injection speed.

As shown in figure 12, thimble 71 can be placed into spring 38, draws at Figure 12.Wheel rim 72 separates an end and the cross rib 40 of spring.Simultaneously, wheel rim 72 helps to prevent the helical spring sidesway, and is convenient to assembling.Thimble has a barrel core 75 and a button-head 76, and this will overcome the problem of the side 37 of spring 38 collision medicated caps 12 or plunger 36.Therefore, in assembling, in adopting assembling automatically, spring 38 curls up on thimble especially, rather than is stuck in medicated cap 12 and barrel promptly manages between 16.In Figure 12, thimble 71 has a chamber 73, wheel rim 72 and wall 74.In one approach, thimble 71 is inserted into spring 38, then both is inserted in the lubricated in advance pipe 16, and having placed core in this pipe is compositions 32 and plunger 36.Like this, can will can not damage in medicated cap 12 interlocks.

The side of claimed capsule inner core 32 and rear end, in order to avoid contact with gastric juice, because gastric juice can cause the excessive swollen of core attached on the bucket sidewall and will prevent the reach of core 32, to keep the sealing contact of this end to end wall 18.In Figure 11, plunger 36 has a planar ends 35, and a cylindrical sidewall 37 is arranged, and on the outer wall 37 of plunger, along its circumference several groove 53 is arranged.Be marked with lubricating oil in the groove, along with core material 32 is consumed, lubricating oil forms sealing at the bucket inwall, so that the continuous sealing state of holding core and bucket end wall 18.Owing to adopted this mazy plunger 36, mobile section is that the spring housing of plunger back can not sealed by plunger, and therefore, for entering of retardance gastric juice, this is a kind of ideal sealing.

Should illustrate, adopt seal capsule, in-core is that activating agent contained in the compositions loaded article is that the fluctuation formula is that pulsed discharges to animal in the incipient stage, and injection speed reduces then, and keeps constant in a long term substantially.The reason of this initial period impulsing is still not clear, but it is believed that it may is due to beginning spring housing internal pressure increases to a certain extent.Said supercharging may be because of variation of temperature, promptly becomes the cud temperature by room temperature and causes for about 39 ℃.It also may be because gas such as carbon dioxide when entering capsule by cud that pressure increases, diffusion velocity by capsule wall greater than nitrogen by speed from the contained air of spring housing to external diffusion caused.

Capsule is applicable to less animal, particularly sheep.

At a specific embodiment that is used for sheep, capsule total length 95.3mm, diameter 18mm, the about 105mm of its chord, cross section 6 * 1mm.The opening diameter diameter of staving end is 6mm.The said wing is connected on the central circular of medicated cap, and this regional diameter is a bit larger tham the width of the wing.

Less sheep is similar to cattle with the capsule administering mode and uses capsular administering mode, and model of action is also similar.Less sheep does not have ribs with the cross section homogeneous of its wing of capsule on whole length, does not resemble cattle yet and be bow action with capsule.Sheep is successfully used with capsule, and has found that it can be detained a very long time in the cud of sheep.

Following formulation examples describes the typical treatment solid composite that can be carried in the slow releasing capsule in detail.

Example 1

One exemplary formulations contains:

Teric12A23 50％

Monensin 40%

Glyceride 10%

With above-mentioned component fusing, the core that is molded into suitable shape is to be suitable for inserting described device.

After the cooling, core is put into plastic body, put plunger and spring again, on body, this process is carried out for the designed full-automatic machine of this device of complete assembling by one the medicated cap gland.

Example 2

If a typical formulation contains antifoaming agent, it comprises:

Gensil800 10％

Monensin 40%

Glyceride 50%

Step according to example 1 prepares said preparation.

Example 3

One typical formulation contains:

Teric12A23 30％

Narasin 40%

Glyceride 30%

Step by example 1 prepares said preparation.

Example 4

If a typical formulation contains antifoaming agent, it comprises:

Silbione70451 20％

Salinomycin 30%

Glyceride 50%

Step according to example 1 prepares above-mentioned preparation.

Example 5

One exemplary formulations contains

Silbione ^70451 20％

Teric ^12A23 40％

Avoparcin 20%

Glyceride 20%

Step by example 1 prepares said preparation.

Example 6

If a typical formulation contains antifoaming agent, it comprises:

Silbione ^70451 20％

Vancomycin 40%

Glyceryl monolaurate 40%

Step according to example 1 prepares above-mentioned preparation.

Example 7

One typical formulation contains:

Teric ^12A23 40％

Mebendazole 20%

Glyceride 40%

Step according to example 1 prepares said preparation.

Example 8

If contain antifoaming agent in the typical formulation, it comprises:

Gensil ^800 20％

Pyrantel Pamoate 20%

Monostearate sorbitol ester 60%

Step according to example 1 prepares above-mentioned preparation.

Example 9

One typical formulation contains:

Teric12A23 20％

Avermectins 20%

Glyceride 60%

Step according to example 1 prepares said preparation.

Example 10

If closed antifoaming agent in the typical formulation, it comprises:

Gensil800 20％

Levamisole 20%

Glyceride 60%

Step by example 1 prepares said preparation.

Example 11

One typical formulation contains:

Monensin 70%

Glyceride 30%

With the monensin fusing, the core that is molded into suitable shape is with in the lucky filling device.

After the cooling, core is put into plastic body, adds upper plug and spring, again the medicated cap gland on body.This process is to assemble for a complete set on the full-automatic machine that described device designs one to carry out.

Example 12

If a typical formulation contains antifoaming agent, it comprises:

Gensil800 20％

Monensin 40%

Glyceryl monostearate 40%

Step by example 1 prepares above-mentioned preparation.

Slow releasing capsule of the present invention is easy to by ruminant using, can discharge the treatment component very effectively, and this capsule is made easily, seepage can not take place during storing and packing.

Claims

1. device of using a compositions to ruminant, this device comprises a seal capsule, there is at least one elasticity to be detained arm on the described capsule outer surface, be detained arm it has a projection on capsular arm surface, arm is flexible that this projection is contacted with a capsular part, and said this part can be penetrated the formation pore by projection.

2. according to the device of claim 1, wherein arm is reinforced.

3. according to the device of claim 1 or 2, wherein said part also comprises the fenestra that the zone by a reduced thickness forms.

4. according to the device of one of claim 1-3, wherein capsule also comprises the medicated cap with a hemisphere portion, is divided into the arm of one with hemisphere portion, near the projection of the junction point of arm and hemisphere portion.

5. use the device of a compositions to ruminant for one kind, this device comprises a tubular capsule, and this capsular end has release aperture, and the other end normally seals, one plunger is arranged in the cylindrical shell, and this plunger is pushed release aperture to by a helical spring, the tight contact plunger of an end of spring, the other end is fixed on the wheel rim of a thimble, said thimble has a core, and an end is conical, forms wheel rim around the other end, the blunt end of thimble is inserted spring, and wheel rim is between spring and the capsule blind end.